Epidemiological studies suggest that early and chronic NSAID consumption (notably ibuprofen) may significantly reduce risk for and delay the onset of AD. However, it is not known whether this association is causal and if so, what mechanisms are involved, which NSAIDs are most efficacious, the dose required or the best time to initiate intervention. NSAID choice may be critical because we have found that selected anti-inflammatory agents actually increase amyloid deposition in animal models. In contrast, we have shown that chronic oral dosing with the over-the-counter medication ibuprofen can reduce or delay the development of inflammation, A13 accumulation and neuritic plaque pathology in transgenic mice (HuAPPsw) carrying a mutant human gene found in familial AD. Ibuprofen induced significant reductions in reactive microglia, IL-lB and dystrophic neurites suggesting that inflammation and secondary neurodegeneration are reduced. Reductions in both soluble and insoluble AG as welt argue that not only inflammation-induced toxicity, but toxicity due to accumulating AG aggregates would also be reduced by this treatment. Coupled with the epidemiology, these data suggest that an inexpensive and relatively safe method for delaying AD and reducing the number of cases by more than half may already be available. We propose to further explore key issues of NSAID prevention of AD pathogenesis including the time of intervention and the role of increased IL-1 (Aim 1), the dose required to delay pathology and the roles of phagocytosis and antichymotrypsin (Aim 2). In Aim 3 we will study the target involved using a non-toxic NSAID treatment linked to reduced heart disease and increased synaptic function and the role of antioxidant activity (Aim 3). We also propose to test in vitro and in vivo several mechanisms of NSAID effects on microglia exhibiting blocked amyloid degradation and hypothesized to be relevant to reducing amyloid load and neuritic plaque pathology (Aim 4). Completion of these studies will lead to a better understanding of the role and control of microglia in AD pathogenesis and contribute to planning clinical trials with approved agents with relatively low toxicity profiles that have already been associated with reduced AD risk in human studies.